A review on biological and chemical diversity in Berberis (Berberidaceae)

Berberis is an important genus and well known in the Indian as well as European systems of traditional medicine. It is used since ancient times for curing eye disease, fever, jaundice, rheumatism, vomiting during pregnancy, kidney and gall balder stones and various other ailments due to the presence of biologically active alkaloid berberine. Action of the root extracts of few species are believed to be as powerful as quinine in the treatment of malarial fever. A plethora of literature pertaining to the taxonomy, biology, chemistry, traditional and ethnic uses of Berberis in different countries and indigenous cultures was collected by both offline (library, journals, textbooks etc.) and online mode (electronic search of available databases). In addition to this, books on traditional medicine and ethno pharmacological knowledge were also referred to extract ancient uses of Berberis in different traditional medicine systems. Most of the folklore, traditional and ethno botanical claims about Berberis species were validated by broad spectrum in vitro and vivo pharmacological studies. The present article summarizes its usage in eye and liver disorder, fever, kidney and gall stones along with anticancer activity. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations.


INTRODUCTION
The genus Berberis has an important place in various traditional systems of medicine worldwide for their efficacious medicinal properties. The ancient Ayurvedic literature of India records uses of Rasaut (Ras = juice; out = frothing and foaming when boiling; hence Rasaut means concentrated juice), an extract of either stem or root of Berberis sp. The specific uses of Rasaut for curing eye diseases and indolent ulcers earned a great fame. In the British Pharmacopoeia, the alkaloid berberine-the active principle in several species of Berberis and Mahonia, has been incorporated for its successful use in the treatment of oriental sore.
The roots of Berberis species are employed as an anti-periodic, diaphoretic and antipyretic, and its action was believed to be as powerful as quinine. The bark is used as a tonic and anti-periodic. This plant is also well proven for cardio vascular, hepato-protective, antimicrobial and anti-cancerous activities. Hence, a review of genus Berberis has been done to put all its activities, ethno botanical claims, pharmacological action along with chemistry. The scientific information compiled in this review is gathered by extensive search of several electronic databases viz. SCOPUS, Google scholar, NOPR, Pub med, Elsevier, ACs, Medline plus, Web of science, etc. Additionally, the library search and ancient medicinal treatises/text books were also referred for gathering information on the traditional uses of Berberis. The review of Berberis was also done with an end in view of identifying the knowledge gaps in traditional uses, pharmacological studies, toxicity profiling, clinical trials and other relevant research in this medicinally important genus. Previous reviews on individual species of Berberis are available, but a comprehensive update on the entire genus is still lacking. This review will help researchers to identify the latent and patent potentials of Berberis and explore further studies on the biological and chemical properties of various species of this genus.

TAXONOMIC HISTORY OF BERBERIS
Berberis belongs to the family Berberidaceae, which was first established by A.L. Jussieu in 1789 as 'Berberides' and was considered one of the most primitive families of Angiosperms having a high number of disjunction or discontinuous genera. There is a general agreement among botanists (Kumazawa, 1938;Hutchinson, 1959;Airy Shaw, 1966;Takhtajan, 1969;Meacham, 1980;Nowicke and Skvarla; that the genera of Berberidaceae are not closely related but are separable into 4 distinct families, namely Lardizabalaceae (Decaisnea, Holboellia, Parvatia), Nandinaceae (Nandina), Podophyllaceae (Podophyllum) and Berberidaceae (Berberis, Mahonia, Epimedium). Berberidaceae was placed in the order Ranales (Bentham and Hooker, 1862). Several other works (Takhtajan, 1969;Cronquist, 1968) placed it in the order Ranunculales, while one worker (Hutchinson, 1959) included this family under a separate order Berberidales.
First taxonomic account of the family Berberidaceae for the Indian subcontinent (Hooker and Thomson, 1875) included six genera and 17 species. A revision of the genus Berberis was made by Schneider during 1905 and1908 and recorded 13 new species and one variety from Indian region. Subsequently (Schneider, 1942) a monograph of section Wallichianae was published in which he recognized 71 species in 8 subsections. Chatterjee (1953) included 68 species of Berberis, 11 species of Mahonia, one species of Epimedium and two species of Podophyllum. In a survey (Ahrendt, 1941/45) the Berberis spp. from Bhutan, Assam, South Tibet, Upper Burma and Northwest Yunnan and later (Ahrendt, 1961) published a detailed revision of Berberis and Mahonia species. He included 52 species with 43 infra specific categories under Berberis and 11 species under Mahonia from the Indian region. It was again revised by including one new species (B. victoriana) from the Indian region (Chamberlain and Hu, 1985). Jafri (1975) while dealing with the Berberidaceae for the Flora of West Pakistan included only one species of Mahonia and 15 species of Berberis from Kashmir region. In a more recent study (Rao and Hajra, 1993) while revising the family for the Flora of India included 54 species of Berberis, one species of Epimedium and 13 species of Mahonia from the present political boundaries of India. Singh et al. (1974Singh et al. ( , 1978 discussed the significance of epidermal structure and leaf architecture in the taxonomy of Berberidaceae. They have studied hardly 5-6 species of the family. Palynologically only five species of Berberis have been studied (Nair, 1965) and chromosome numbers in only nine species with five infraspecific categories of Berberis and three species of Mahonia have been reported (Kumar and Subramaniam, 1986). Some commercially important Berberis spp. from Indian region is shown in Figure 1.

ETHNOBOTANICAL AND
TRADITIONAL USES There has been an increasing interest towards the scientific study of human-plant interaction in the natural environment among the botanists, social scientists, anthropologists, practitioners of indigenous systems of medicine. Jain (1981) undertook intensive field study among tribes of central India and devised methodology for ethno-botany, particularly in the Indian context. Different species of genus Berberis are used ethno botanically and medicinally by various tribes and in different traditional medical systems. A detailed pharmacognostic study of some common Himalayan Berberis species has been done by Srivastava et al., 2001Srivastava et al., , 2004Srivastava et al., , 2006Srivastava et al., , 2010Singh et al., 2009Singh et al., , 2012Rawat, 2013, 2014. The ethno botanical uses of Berberis by different tribal communities in India and some other countries are provided in Table 1.

OF BERBERIS SPECIES
Berberis has diverse pharmacological potential. Various pharmacological activities of the Berberis species make them an important part of polyherbal formulations for the treatment of several diseases and disorders (Figure 2,

B. aristata
In Raithal locality of Uttarkashi (Uttaranchal), India, Rasaut-a popular medicine prepared for eye disorders from the roots of B. aristata Kirtikar and Basu, 1935;Anonymous, 1948;Hayashi, 1950;Uniyal, 1964 In Kumaon region of India, the decoction of root bark from B. aristata and B. asiatica is used for curing eye troubles and boils. A sauce is also prepared from its acidic flower buds Shah and Joshi, 1971 The decoction of the root of B. aristata is used in piles, gastric disorders and other allied complaints by Tibetan people and the plant is known there as Kershuen Chauhan et al., 1978/79 Local inhabitants of DehraDun district of Uttaranchal, India use B. aristata as fish poison Jain and Suri, 1979/80 Used in snake and scorpion bite by the tribal's in Uttaranchal, India Mittre, 1981

B. asiatica
Inhabitants of Assam, India, use root extract with butter for the treatment of bleeding piles. About 2 ml of the extract of its root is taken with butter daily for two weeks Bhattacharjee et al., 1980 B. lycium In Lahul province of HP, India, B. lycium and B. pachyacantha fruit is used medicinally for stomachache. Roots yield a yellow dye for textiles. The twigs are important in ceremonials of Priests and Lamas. In the Burial ceremony, barberry nails are used. For Losar (New Year) celebrations barberry wood and buck wheat straw is used. Koetz and Walter, 1979 In Rajouri district of Jammu, India, fruits of B. lycium are used as coagulant, branches made into broom for removing husk from grains Virjee et al., 1984

B. petiolaris
In Kumaon region of Uttaranchal hills, India, the flowers of B. petiolaris are mixed with spinach, mashed and taken as salad Bhargava, 1959

B. tinctoria
Todas of Nedimand tribes, Nilgiris, India, grind the roots of B. tinctoria with water and administer it for stomachache, especially in the treatment of worms. Bark is used for stomach disorders of Buffaloes, along with butter. Fruits are eaten by Kotas of Kollimalai Abraham, 1981 B. wallichiana B. wallichiana is used by the tribes of various ethnic groups like Nishi, Apatani, Hill-Miri, Adi, etc. of Subansiri district of Arunachal Pradesh, India. A bunch of spines is used for tattooing on chin and forehead. The tattoo locally called te is significant and is a traditional custom. Skin is pricked with spines. A mixture of rice starch and root is applied on the wound. The rice starch pierces the skin and the root gives the colour Pal, 1984

B. jaeshkeana
Root extract of B. jaeshkeana and B. kumaonesis, commonly called as Kingora and Jhuri respectively in Garhwal Himalayas, India, used as an astringent, diuretic, blood purifier and alternative. It is also used in eye disorders, menorrhea, jaundice and skin diseases by the local tribes Gaur et al., 1976

B. vulgaris
Berries are used for sore throat and fever. Poultice of pounded root or bark used for sore throat Speck, 1998 Cold and compound decoctions of berries are taken in fever Tantaquidgeon, 1928 Decoction of leaves taken three times a day for jaundice Carr and Carlos, 1945 Bark and root is used for ulcerated gums and sore throat Chandler et al., 1979 Roots of B. vulgaris are boiled in water and decoction is used in both human and cattle for the treatment of internal injuries and also used for tanning skin

CHEMICAL DIVERSITY IN BERBERIS
Isoquinoline alkaloids are the major bioactive constituents in Berberis (Figure 3). Berberine is a major representative of the protoberberine alkaloids which are a structural class of organic cations, characteristically yellow, having four linked benzene rings with a nitrogen atom joining two rings pairs, and modified via two oxygen atoms at each end. A vast array of alkaloids has been isolated from various Berberis species, among which, berberine, berbamine, Palmitine, jatrorrhizine and isotetrandrine are the most common ones (Figure 4).
The histological distribution of berberine has been well studied; alkaloids of Berberis are located chiefly in the cortical tissues of the roots and stems. The bark of old roots contains the highest concentration of alkaloids. In the upper parts of the stem, concentration is low and in young leaves alkaloids could not be detected (Greathouse and Rigler, 1940;Greathouse and Watkins, 1938). Histo-logical distribution of berberine, umbellatine and nepiotime has also been examined in Indian species of Berberis (Chatterjee, 1952;Chatterjee et al., 1954). Mean value of berberine content for young actively growing shoots is 0.04 % and for young parenchymatous roots is 1.41 %. Thus there is a progressive increase in the berberine content of the plants with an increase in age.
Chemical analysis of the traditional preparation 'Rasaut' from Punjab market showed 1.67-4.26 % total alkaloid. The yield of Rasaut from B. lycium was found to be 15.4 % w/v and contained about 9.4 %w/v berberine (Anonymous, 1948).
Berberine exists in three tautomeric forms (I-III) in solution. Later on, these tautomeric structures and the evidence for the existence and structures of the ammonium (I) and pseudo-base form (II) were established (Anonymous, 1967). Chemical diversity of various Berberis species is illustrated in Table 3.
Roots Tomita and Yong, 1960;Du and Francis, 1974 Species Isolated active principals Plant parts Reference

Stem bark
Fruits Tiwari and Masood, 1979;Majumdar and Saha, 1978 Vereskovskii  Hussain, 1992 CONCLUSION AND FUTURE PROSPECTIVE During the last few decades there has been an increase in the study of medicinal plants and their traditional use in different parts of the world. Reports of the folk medicine followed by critical scientific evaluation have given to the world newer sources as corrective, preventive and upto some extent curative measures in various diseases. Berberis species are among the most important traditional herbs with a vast array of pharmacological activities. The present review summarizes the taxonomic, ethno-botanical, pharmacognostic, photochemical and pharmacological claims of Berberis species. Literature on Phyto-chemistry reveals that the species are rich in alkaloids, of which biologically active 'Berberine' is the major and potential one.
This review is a comprehensive documentation of various species belonging to this genus and their therapeutic potentials in the present context. Previous pharmacological studies on Berberis and its isolated alkaloids revealed more potential towards cardio vascular, hepato-protective, antimicrobial and anticancer activities. Recent trend in research on Berberis species, however directed the workers to focus more towards oncology, toxicological studies and clinical trials. This review will be useful for researchers to approach the newer avenues by exploring varied pharmacological activities like anti diarrheal, antispasmodic, anti malarial, etc., which in turn will be more beneficial in developing myriads of scientifically validated herbal formulations containing naturally occurring biodynamic compounds.